Systemic Hypoxemia Induces Cardiomyocyte Hypertrophy and Right Ventricular Specific Induction of Proliferation.

BACKGROUND: A recent study suggests that systemic hypoxemia in adult male mice can induce cardiac myocytes to proliferate. The goal of the present experiments was to confirm these results, provide new insights on the mechanisms that induce adult cardiomyocyte cell cycle reentry, and to determine if hypoxemia also induces cardiomyocyte proliferation in female mice. METHODS: EdU-containing mini pumps were implanted in 3-month-old, male and female C57BL/6 mice. Mice were placed in a hypoxia chamber, and the oxygen was lowered by 1% every day for 14 days to reach 7% oxygen. The animals remained in 7% oxygen for 2 weeks before terminal studies. Myocyte proliferation was also studied with a mosaic analysis with double markers mouse model. RESULTS: Hypoxia induced cardiac hypertrophy in both left ventricular (LV) and right ventricular (RV) myocytes, with LV myocytes lengthening and RV myocytes widening and lengthening. Hypoxia induced an increase (0.01±0.01% in normoxia to 0.11±0.09% in hypoxia) in the number of EdU+ RV cardiomyocytes, with no effect on LV myocytes in male C57BL/6 mice. Similar results were observed in female mice. Furthermore, in mosaic analysis with double markers mice, hypoxia induced a significant increase in RV myocyte proliferation (0.03±0.03% in normoxia to 0.32±0.15% in hypoxia of RFP+ myocytes), with no significant change in LV myocyte proliferation. RNA sequencing showed upregulation of mitotic cell cycle genes and a downregulation of Cullin genes, which promote the G1 to S phase transition in hypoxic mice. There was significant proliferation of nonmyocytes and mild cardiac fibrosis in hypoxic mice that did not disrupt cardiac function. Male and female mice exhibited similar gene expression following hypoxia. CONCLUSIONS: Systemic hypoxia induces a global hypertrophic stress response that was associated with increased RV proliferation, and while LV myocytes did not show increased proliferation, our results minimally confirm previous reports that hypoxia can induce cardiomyocyte cell cycle activity in vivo.

In-Vitro Sorbent-Mediated Removal of Edoxaban from Human Plasma and Albumin Solution.

BACKGROUND AND OBJECTIVE: Based on previous experience of sorbent-mediated ticagrelor, dabigatran, and radiocontrast agent removal, we set out in this study to test the effect of two sorbents on the removal of edoxaban, a factor Xa antagonist direct oral anticoagulant. METHODS: We circulated 100 mL of edoxaban solution during six first-pass cycles through 40-mL sorbent columns (containing either CytoSorb in three passes or Porapak Q 50-80 mesh in the remaining three passes) during experiments using human plasma and 4% bovine serum albumin solution as drug vehicles. Drug concentration was measured by liquid chromatography-tandem mass spectrometry. RESULTS: Edoxaban concentration in two experiments performed with human plasma dropped from 276.8 to 2.7 ng/mL and undetectable concentrations, respectively, with CytoSorb or Porapak Q 50-80 mesh (p = 0.0031). The average edoxaban concentration decreased from 407 ng/mL ± 216 ng/mL to 3.3 ng/mL ± 7 ng/mL (p = 0.017), for a removal rate of 99% across all six samples of human plasma (two samples) and bovine serum albumin solution (four samples). In four out of the six adsorbed samples, the drug concentrations were undetectable. CONCLUSION: Sorbent-mediated technology may represent a viable pathway for edoxaban removal from human plasma or albumin solution.

Removal of dabigatran using sorbent hemadsorption.

BACKGROUND: The Redual PCI trial has demonstrated the safety of dabigatran and ticagrelor or clopidogrel combination in preventing strokes in patients with atrial fibrillation. There was 15.4% risk of hemorrhage in the dabigatran/ticagrelor or clopidrogel arm, lower than that of triple therapy with warfarin, aspirin and ticagrelor or clopidogrel. While idarucizumab is an effective antidote for dabigatran, there is no good method for antagonizing both dabigatran and ticagrelor. We tested in this study a hemadsorbtion method for removing dabigatran that we had previously successfully applied in the removal of ticagrelor from human blood. METHODS: 100 mL 4% BSA solution pre-incubated with dabigatran was passed through 10, 20 and 40 mL sorbent columns and dabigatran concentration was measured from the affluent and effluent solution using LC-MS/MS. For testing the effect of dabigatran removal on the aPTT value one human volunteer was administered oral dabigatran etexilate mesilate 150 mg. Plasma was collected 4 h after dabigatran administration and then in three experiments 20 mL of collected plasma was circulated through three different 10 mL CytoSorb columns over a duration of 5 min. aPTT was measured from plasma at baseline prior to drug administration, then post blood collection (mixed plasma) and from the adsorbed plasma as well. RESULTS: Dabigatran concentration, as measured by LC-MS/MS, decreased from 1456 ±â€¯331 nM (greater than the therapeutic level of 743 nM) to 67 ±â€¯59 nM (P = 0.002) with the 10 mL CytoSorb column, while with the 40 mL column it dropped to undetectable levels. In one human volunteer experiment the aPTT was on average 29.2 ±â€¯0.4 in the 3 baseline samples, 34.7 ±â€¯1.8 s after oral dabigatran (mixed plasma), and 25 ±â€¯0.7 s after plasma was passed through CytoSorb (adsorbed plasma) (P = 0.000025 and 0.0000002 for comparison between baseline plasma and mixed plasma, as well as the dabigatran mixed plasma and post-adsorption values respectively). CONCLUSION: Dabigatran is robustly removed by a sorbent hemadsorption method already proven successful for the P2Y12 receptor antagonist ticagrelor. Dabigatran removal restores the aPTT to below baseline values, suggesting that sorbent hemadsorption could clinically reverse the anticoagulant effect of this drug.